Evaluation of acute myeloid leukemia blast percentage on MethylC-Capture Sequencing results.
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ABSTRACT:
SUBMITTER: Yang E
PROVIDER: S-EPMC8011402 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Clinical and genetic features incompletely predict outcome in acute myeloid leukemia (AML). The value of clinical methylation assays for prognostic markers has not been extensively explored. We assess the prognostic implications of methylC-capture sequencing (MCC-Seq) in patients with de novo AML by integrating DNA methylation and genetic risk stratification. MCC-Seq assessed DNA methylation level in 44 samples. The differentially methylated regions associated with prognostic genetic information were identified. The selected prognostic DNA methylation markers were independently validated in two sets. MCC-Seq exhibited good performance in AML patients. A panel of 12 differentially methylated genes was identified with promoter hyper-differentially methylated regions associated with the outcome. Compared with a low M-value, a high M-value was associated with failure to achieve complete remission (p = 0.024), increased hazard for disease-free survival in the study set (p = 0.039) and poor overall survival in The Cancer Genome Atlas set (p = 0.038). Hematopoietic stem cell transplantation and survival outcomes were not adversely affected by a high M-value (p = 0.271). Our study establishes that MCC-Seq is a stable, reproducible, and cost-effective methylation assay in AML. A 12-gene M-value encompassing epigenetic and genetic prognostic information represented a valid prognostic marker for patients with AML.
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Project description:The purpose of the present work was to determine the incidence and clinical implications of somatic EZH2 mutations in 714 patients with de novo acute myelogenous leukemia by sequencing the entire coding region. EZH2 mutations were identified in 13/714 (1.8%) of AML patients were found to be more common in males (P = 0.033). The presence of EZH2 mutations was significantly associated with lower blast percentage (21-30%) in bone marrow (P<0.0001) and -7/del(7q) (P = 0.025). There were no differences in the incidence of mutation in 13 genes, ASXL1, CBL, c-KIT, DNMT3A, FLT3, IDH1, IDH2, MLL, NPM1, NRAS, RUNX1, TET2, and WT1, between patients with and without EZH2 mutations. No difference in complete remission, event-free survival, or overall survival was observed between patients with and without EZH2 mutation (P>0.05). Overall, these results showed EZH2 mutation in de novo acute myeloid leukemia as a recurrent genetic abnormality to be associated with lower blast percentage in BM and -7/del(7q).
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Project description:BackgroundAzacitidine is an hypomethylating agent widely adopted for the treatment of acute myeloid leukaemia (AML) in patients who are ineligible for curative-intent chemotherapy. Patients with low bone marrow blast counts (<?30%) experience improved survival with azacitidine, but the benefits are significantly lower in patients with?>?30% blasts in the bone marrow. As such, there is uncertainty around the economic benefit of azacitidine in patients with higher blast counts.ObjectiveWe present a cost-utility analysis of azacitidine in patients with AML with?>?30% blasts to determine the economic value of azacitidine in this patient population from the perspective of a third-party payer.MethodsA Markov model was developed with a time horizon of 25 months divided into 22 cycles of 35 days each. The cost utility of azacitidine was compared with that of conventional care regimens (which include best supportive care, low-dose cytarabine and induction chemotherapy). A Canadian public healthcare system perspective was selected.ResultsIn the base case, the incremental cost per quality-adjusted life-year gained (incremental cost-effectiveness ratio [ICER]) for azacitidine compared with conventional care regimens was $Can160,438, year 2018 values. The estimated ICER was insensitive to a longer time horizon but sensitive to the cost of azacitidine and to assumptions relating to survival in both treatment regimens, although the ICER always remained greater than Can$80,000 in all scenarios.ConclusionAzacitidine is unlikely to be cost effective given that the estimated ICER exceeds the willingness to pay commonly used in the Canadian healthcare system.
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Project description:Acute myeloid leukemia (AML) is one of the most common acute leukemias in adults and children, yet significant numbers of patients relapse and die of disease. In this study, we identify the dependence of AML blasts on arginine for proliferation. We show that AML blasts constitutively express the arginine transporters CAT-1 and CAT-2B, and that the majority of newly diagnosed patients' blasts have deficiencies in the arginine-recycling pathway enzymes argininosuccinate synthase and ornithine transcarbamylase, making them arginine auxotrophic. BCT-100, a pegylated human recombinant arginase, leads to a rapid depletion in extracellular and intracellular arginine concentrations, resulting in arrest of AML blast proliferation and a reduction in AML engraftment in vivo. BCT-100 as a single agent causes significant death of AML blasts from adults and children, and acts synergistically in combination with cytarabine. Using RNA sequencing, 20 further candidate genes which correlated with resistance have been identified. Thus, AML blasts are dependent on arginine for survival and proliferation, as well as depletion of arginine with BCT-100 of clinical value in the treatment of AML.
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Project description:The deregulation of lineage control programs is often associated with the progression of haematological malignancies. The molecular regulators of lineage choices in the context of tyrosine kinase inhibitor (TKI) resistance remain poorly understood in chronic myeloid leukemia (CML). To find a potential molecular regulator contributing to lineage distribution and TKI resistance, we undertook an RNA-sequencing approach for identifying microRNAs (miRNAs). Following an unbiased screen, elevated miRNA182-5p levels were detected in Bcr-Abl-inhibited K562 cells (CML blast crisis cell line) and in a panel of CML patients. Earlier, miRNA182-5p upregulation was reported in several solid tumours and haematological malignancies. We undertook a strategy involving transient modulation and CRISPR/Cas9 (clustered regularly interspersed short palindromic repeats)-mediated knockout of the MIR182 locus in CML cells. The lineage contribution was assessed by methylcellulose colony formation assay. The transient modulation of miRNA182-5p revealed a biased phenotype. Strikingly, Δ182 cells (homozygous deletion of MIR182 locus) produced a marked shift in lineage distribution. The phenotype was rescued by ectopic expression of miRNA182-5p in Δ182 cells. A bioinformatic analysis and Hes1 modulation data suggested that Hes1 could be a putative target of miRNA182-5p. A reciprocal relationship between miRNA182-5p and Hes1 was seen in the context of TK inhibition. In conclusion, we reveal a key role for miRNA182-5p in restricting the myeloid development of leukemic cells. We propose that the Δ182 cell line will be valuable in designing experiments for next-generation pharmacological interventions.
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Project description:Standard treatment for higher risk myelodysplastic syndromes, chronic myelomonocytic leukemia and low blast acute myeloid leukemia is azacitidine. In single arm studies, adding lenalidomide had been suggested to improve outcomes. The ALLG MDS4 phase II trial randomized such patients to standard azacitidine or combination azacitidine (75mg/m2/d days 1 to 5) with lenalidomide (10mg days 1-21 of 28-day cycle from cycle 3) to assess clinical benefit (alive without progressive disease) at 12 months. A total of 160 patients were enrolled; median age 70.7 years (range 42.5-87.2), 31.3% female with 14% chronic myelomonocytic leukemia, 12% acute myeloid leukemia and 74% myelodysplastic syndromes. Adverse events were similar in both arms. There was excellent delivery of protocol therapy (median azacitidine cycles 11 both arms) with few dose reductions, delays or early cessations. At median follow up 33.1 months (range 0.7-59.5), the rate of clinical benefit at 12 months was 65% azacitidine arm and 54% lenalidomide+azacitidine arm (P=0.2). There was no difference in clinical benefit between each arm according to WHO diagnostic subgroup or IPSS-R. Overall response rate was 57% in azacitidine arm and 69% in lenalidomide+azacitidine (P=0.14). There was no difference in progression- free or overall survival between the arms (each P>0.12). Although the combination of lenalidomide and azacitidine was tolerable, there was no improvement in clinical benefit, response rates or overall survival in higher risk myelodysplastic syndrome, chronic myelomonocytic leukemia or low blast acute myeloid leukemia patients compared to treatment with azacitidine alone. This trial was registered at www.anzc-tr.org.au as ACTRN12610000271000.
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